Abstract
BMI1 plays critical roles in maintaining the self-renewal of hematopoietic, neural, intestinal stem cells, and cancer stem cells (CSCs) for a variety of cancer types. BMI1 promotes cell proliferative life span and epithelial to mesenchymal transition (EMT). Upregulation of BMI1 occurs in multiple cancer types and is associated with poor prognosis. Mechanistically, BMI1 is a subunit of the Polycomb repressive complex 1 (PRC1), and binds the catalytic RING2/RING1b subunit to form a functional E3 ubiquitin ligase. Through mono-ubiquitination of histone H2A at lysine 119 (H2A-K119Ub), BMI1 represses multiple gene loci; among these, the INK4A/ARF locus has been most thoroughly investigated. The locus encodes the p16INK4A and p14/p19ARF tumor suppressors that function in the pRb and p53 pathways, respectively. Its repression contributes to BMI1-derived tumorigenesis. BMI1 also possesses other oncogenic functions, specifically its regulative role in DNA damage response (DDR). In this process, BMI1 ubiquitinates histone H2A and γH2AX, thereby facilitating the repair of double-stranded DNA breaks (DSBs) through stimulating homologous recombination and non-homologous end joining. Additionally, BMI1 compromises DSB-induced checkpoint activation independent of its-associated E3 ubiquitin ligase activity. We review the emerging role of BMI1 in DDR regulation and discuss its impact on BMI1-derived tumorigenesis.
Highlights
The BMI1 (B lymphoma Mo-MLV insertion region 1) gene was identified as a collaborating oncogene with Myc in the tumorigenesis of B cell lymphoma in 1991 [1,2]
Histone H2A-K119Ub is a classic epigenetic mark that is associated with gene silencing [103,104]; H2A-K119Ub is an abundant histone modification, which is produced by Polycomb repressive complex 1 (PRC1), and can constitute up to 10% of cellular histone H2A [3,4,6,105]
This possibility is supported by experimental evidence showing that BMI1 recruitment to DSB
Summary
The BMI1 (B lymphoma Mo-MLV insertion region 1) gene was identified as a collaborating oncogene with Myc in the tumorigenesis of B cell lymphoma in 1991 [1,2]. BMI1 stimulates the E3 ubiquitin ligase activity of PRC1 via binding and stabilizing the catalytic subunit RING2/RING1b [3] It plays a major role in PRC1-catalyzed mono-ubiquitination of histone H2A at lysine (K) 119 (H2A-K119Ub) [3,4,5,6]. BMI1 plays a critical role in the self-renewal of NSC during development through inhibition of p21CIP1 [36]; BMI1 regulates the self-renewal of ISCs through suppression of the INK4A/ARF locus and at the same time, both the Notch and Wnt pathways regulate BMI1 expression in this process [37]. While BMI1 suppresses PTEN gene expression in nasopharyngeal epithelial cells [41], PTEN is able to inhibit BMI1 function via a physical association [44] This association does not require PTEN’s PIP3 [phosphatidylinositol (3,4,5)-trisphosphate] phosphatase activity and occurs inside the nucleus [44]. For other processes contributing to BMI1-stimulated tumorigenesis, please see the elegant reviews by Siddique and Saleem and by Benetatos et al [33,47]
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